Abstract

Vesicoureteral reflux (VUR) in children is often treated with antimicrobials for
prolonged durations, which often leads to antimicrobial resistance. In this context,
this review article discusses the use of endoscopic injection in VUR as a safe and
efficacious option for these children.
The literature pertaining to VUR- its clinical manifestation and management,
antibiotic resistance- with special reference to management of VUR, and
endoscopic dextranomer/hyaluronic acid gel injection for management of VUR
was reviewed by identifying key words in a PubMed search.
Vesicoureteral reflux is managed using antibiotic prophylaxis, urotherapy,
or surgical correction (open, endoscopic injection therapy, or laparoscopic).
Continuous antibiotic prophylaxis for urinary tract infections in VUR can lead to
antibiotic resistance. Urotherapy cures about 75% of cases with dysfunctional
voiding and the rest have to be managed at specialized centers. While open
surgery provides relief of VUR and related complications in majority, it requires
hospitalization. Endoscopic injection of dextranomer/hyaluronic acid gel into
the submucosa of bladder or ureter near ureteral orifice increases the tissue
bulk and creates a valve function. Various studies show the efficacy and safety
of endoscopic injection of dextranomer/hyaluronic acid gel in VUR. The use of
endoscopic injection being a non-invasive modality, can be performed in children
with VUR in the outpatient department, precluding hospitalization.
In view of the threat of developing antimicrobial resistance and also realising
the need for definitive treatment of VUR, endoscopic injection is an efficacious
and safe option in primary VUR.

Introduction

Antimicrobial therapy has become
one of the pillars of modern
medicine over the last 60 years.
The fear of death due to microbial
infection is now almost obsolete in the
developed world due to availability
of various antimicrobial agents, but
on the other side, this is threatened
by the development of resistance to
antimicrobials. The arrival of these
antimicrobial agents marked the
beginning of an era of optimism and
enthusiasm regarding conquest over
infectious diseases. This optimism
started fading with the development of
resistance to these agents in bacteria.1
This is particularly a major problem
in developing countries where the
burden of infections is very high and
cost constrains the replacement of older antimicrobial agents. The infectious
disease burden in India is one of
the highest in the world; therefore,
antimicrobial agents have a role to play
in limiting morbidity and mortality in
India. 2

Primarily, drug resistance has been
recognized as a medical problem. When
antimicrobial agents are used either
in human beings or animals, there
is always a risk of the development
and spread of antibiotic resistance in
bacteria. Therefore, there is need of
each country to adopt strategies fit to
its own condition. 2

Antimicrobial Resistance – A Global
Threat

Antimicrobial resistance is a
major problem that strikes at the
centre of infectious disease control.
Antimi crobial resi stance and its
global spread threaten the continued
effectiveness of antimicrobials and also
risks global health security.

Infections caused by multidrugresistant
(MDR) bacteria are often
as sociat ed with prolonged and
expensive hospitalization. The most
important factor behind the evolution
of drug resistance in bacteria is the drug
selection pressure, which involves use
of drugs in both human and animals.

In many cases, these infections lead
to higher morbidity and mortality.
Multi-drug resistant organisms have
been an epidemiological concern as
they may spread locally, regionally or
globally through individual contacts,
poor sanitation, travel or food chain.3

For antimicrobial resistance to
become a clinical problem, three events
must occur.

First, an individual pathogenic
bacterium must acquire resistance
to the antimicrobial agent in
question. This could occur by a
spontaneous mutation in one of
its genes, which might make a
target protein less susceptible
to the antibiotic by modification
of the antibiotic binding site.
Alternatively, the bacterium could
gain a gene encoding antimicrobial
resistance via horizontal transfer
of deoxyribonucleic acid from a
different bacterial strain.

Second, the newly resistant
bacterium must multiply in such a
fashion that its resistance-encoding
gene spreads in the local bacterial population and cannot be wiped
out through fluctuations in the
number of organisms carrying this
gene.

Third, the resistant bacterial
strain must spread beyond the
local bacterial population where
it originated, until it infects a
significant number of humans and
becomes clinically significant. 4

Currently although antimicrobial
resistance is a grave threat in many
places in India, the problem remains
largely unrecognized mainly because
there are not much studies published
and also because the surveillance
system in India does not match up the
magnitude of the problem . The threat
of antimicrobial resistance came into
light in a big way only when the New
Delhi metallo-β-lactamase-1 (NDM1)
was first reported in 2009. New Delhi
metallo-β-lactamase-1 is an enzyme
produced by the gene blaNDM1,
carried on plasmids which could be
transferred to many bacterial species,
for example Klebsiella pneumoniae and
Escherichia coli, thereby conferring
resistance to multiple antibiotics,
including carbapenems. 2

The first epidemic reported to
be caused by an antibiotic-resistant
bacterial strain was by chloramphenicol
resistant Salmonella typhi in 1972 in
Mexico.5 Subsequent outbreak was
reported by the chloramphenicolresistant
S. typhi strains in Kerala,
India. Since then, MDR S. typhi strains
showing resistance to chloramphenicol,
ampicillin, and trimethoprim have been
reported in the Indian subcontinent,
Southeast Asia, and Africa. 6

New Delhi metallo-β-lactamase-1,
a metallo-beta-lactamase (MBL) ,
belonging to the family of
carbapenemases, was first identified
in isolates of K. pneumoniae and E.
coli, both recovered from a patient in
Sweden after his treatment in a hospital
in New Delhi, India.2 Thereafter,
studies reported NDM1 from a tertiary
centre in Mumbai, following isolation
of MDR Enterobacteriacae in other cities.

Thereafter , resistance to a
further wide range of antibiotics
has been reported among hospitalacquired
gram-negative organisms
(Acinetobactor, Pseudomonas, Klebsiella,
E. coli, Salmonella, Neisseria gonorrhoeae).
The prevalence of extended-spectrum
beta-lactamase (ESBL)-producing Enterobacteriaceae is increasing
worldwide and infections with ESBL
producing E. coli are posing major
threat in many countries including
India.7

Immediate strategies to combat
such emerging landscape of antibiotic
resistance should include rational use
of antimicrobial agents, public health
education, behavioural change and
communication strategies.

Several disease conditions
characterised by infections are treated
with the use of antibiotics. However,
injudicious use of antibiotics in these
disease conditions leads to development
of antibiotic resistance in these patients.
One such condition is vesicoureteral
reflux (VUR) in which patients suffer
from urinary tract infections (UTIs).

Vesicoureteral Reflux and its Clinical
Manifestations

Vesicoureteral reflux is characterized
by the retrograde flow of urine from the
bladder to the upper urinary tract.

The prevalence of VUR is estimated
to be around 0.4% to 1.8%. The
prevalence of VUR is higher in siblings
of patients with VUR (46%), children
with recurrent UTI (30%), infants with
prenatal hydronephrosis (16%), and the
presence of congenital anomalies of the
urinary tract such as posterior urethral
valves (60%), cloaca (60%), and duplex
kidney (46%). 8

Children , who present with
hydronephrosis in intrauterine
life , identified prenatally via
ultrasonography; often present with
clinical UTI in early years of life.9

The diagnosis of UTI in children
can be difficult. Children often present
with nonspecific clinical features.
Pyelonephritis in young children
usually manifest with abdominal
discomfort rather than with the classic
flank pain and tenderness observed in
adults.10

Globally, VUR is considered a crucial
etiological factor for post-UTI renal
scarring in children. Vesicoureteral
reflux predisposes children to UTI and
pyelonephritis, and both are associated
with significant renal scarring.11

Management of VUR

The goals of management of VUR
include the prevention of reflux
and prevention of pyelonephritis,
ref lux nephropat h y , and ot her
complications of reflux. The various treatment strategies include antibiotic
prophylaxis, urotherapy (correction
of voiding dysfunction), and surgical
correction (open, endoscopic injection
therapy, or laparoscopic).12

Antibiotic prophylaxis

The knowledge of the relationship
between renal scarring, UTI, and VUR
paved the path for the emergence of the
clinical use of prophylactic antibiotics
in the early 1970s. This was largely due
to the work of Normand and Smellie,
who had shown a decrease in the
incidence of UTI in children with VUR
on Continuous Antibiotic Prophylaxis
(CAP). As a clinical strategy, CAP
became the recommendation of the
American Urological Association
guideline in 1997.13

However, the patients suffering from
primary VUR generally belong to the
paediatric age group and injudicious
and long-term usage of antibiotics for
prevention and/or treatment of these
UTIs often is associated with the risk
of onset of antibiotic resistance in these
patients.

Concern is growing among medical
practitioners about the long-term use of
CAP in VUR patients. Poor compliance
to antibiotic regime is also common.
These facts against long-term antibiotic
use have led to a rethinking about the
use of CAP in these children.

Urotherapy or bladder training

It is a non - surgical , non -
pharmacological treatment of lower
urinary tract symptoms of neurogenic
and non-neurogenic bladders. It
mainly includes - pelvic floor training
and biofeedback. Urotherapy cures
about 75% of children with overactive
bladder and dysfunctional voiding.
Non-responders should be referred
to specialized centres for further
urodynamic investigations.14

Surgery

Decisions for surgery are based
on numerous factors like patient’s
age, health, grade of reflux, clinical
course of the disease, compliance to
antibiotics, presence of renal scarring,
and parental preference. Prevention of
febrile UTI or pyelonephritis is one of
the major goals of surgical management.
Surgical treatment of VUR reduces the
occurrence of pyelonephritis. Patients
with recurrent UTI and/or persistent
reflux benefit most from surgery.

Open surgery prevents reflux by increasing the length of the intravesical
ureter and thereby faci l i t a t i n g
compression of the ureter against the
detrusor muscle during the urinary
bladder filling. In endoscopic repair,
the dextranomer/hyaluronic acid gel
is injected into the submucosa of
either the bladder or the ureter near
the ureteral orifice. As a result, the
ureteral orifice closes because of the
increase in tissue bulk, creating a valve
function. This allows coaptation of the
ureter during filling and contraction of
the bladder, making it more difficult
for urine to reflux, or flow, back into
the ureter.

Open surgery generally requires
hospitalization for management of
post-operative pain as well as for
temporary urinary catheter drainage
whereas the endoscopic repair is an
outpatient procedure (some surgeons
even prefer the minor operation theatre)
with minimal post-operative pain and
no need for urinary catheter.15

Antibiotic Prophylaxis in
Vesicoureteral Reflux and
Development of Antibiotic Resistance

There has been strong evidence
for overuse of antibiotics in children
suffering from paediatric urological
disorders. Febrile UTI is one of the
most serious bacterial infections in the
paediatric age group because of the
involved risk of renal scarring with
permanent damage to the kidneys in
about 5%.16

As reinfection in these children is
very common, physicians prescribe
daily low-dose antibiotic prophylaxis to
prevent further UTIs in these children
especially those with VUR and prenatal
hydronephrosis.17

In 2010, a Cochrane Review studied
the efficacy and safety of long-term
chemoprophylaxis to prevent recurrent
UTIs in the paediatric age group. The
Cochrane Review concluded that even
though long-term chemoprophylaxis
reduces the risk of recurrent UTIs in
children, there is a simultaneous highly
increased risk of microbial resistance.18

The choice of antibiotic for
chemoprophylaxis is also very
crucial. Cheng (2008) found that
children receiving cephalosporins for
prophylaxis tend to develop ESBLproducing
bacteria or MDR bacteria for
breakthrough UTIs; therefore, it was
suggested that these antibiotics are not
suitable for prophylactic use in patients with VUR.19

Also compliance with
chemoprophylaxis is often poor,
particularly in the lower socioeconomic
strata and poor compliance leads
to increased risk for antibiotic
resistance. Younger age, recurrent
hospitalizations, and visits to the
physicians have been observed to be
associated with improved compliance,
suggesting that probably compliance
to chemoprophylaxis may be improved
through increased patient contact with
the healthcare system.

Appropriate prescribing o f
antibiotics is necessary to improve
patient outcomes and to help prevent
the emergence of antibiotic resistance.
Although there has been a reduction in
use of antibiotics in the United States
by 17% in the last few years, there is
still evidence of antibiotic overuse
and misuse (The Center for Disease
Dynamics, Economics and Policy,
2013).20

With respect to paediatric urology,
the resistance pattern of uropathogens
has been constantly evolving. When
compared with the years 2002-
2004, in 2009 the resistance rates of
trimethoprim/sulfamethoxazole (TMP/
SMX) for E. coli paediatric urinary
tract infections (UTIs) increased in
both boys (from 23% up to 31%) and
girls (from 20% up to 23%). Also a
ten-time increase in E. coli resistance
to ciprofloxacin in boys (from 1% in
2002–2004 to 10% in 2009) and girls
(from 0.6% to 4%) in paediatric UTIs
was reported.21 Moreover, paediatric
hospitalizations for pyelonephritis
in California increased from 17 per
100,000 children in 1985 to 31 per
100,000 children in 2006.22

There is often misuse of certain
antibiotics in the outpatient treatment
of paediatric UTIs. There has been a
strong shift towards using the newer
antibiotic classes, including macrolides
and fluoroquinolones. There were fewer
overall prescriptions for antibiotics in
2010 as compared to 1999, but the
prescription for macrolides increased
from 22% to 27%; similarly, the
prescription for quinolones increased
from 9% to 12%. Increased use of an
antibiotic class can markedly accelerate
the rise of bacterial resistance.23

Irrational empirical antibiotic
therapy may contribute to increased
morbidity and increased expenses due to the long durations of the antibiotic
treatment and recurrent hospital
admissions.24 Based on clinical and in
vitro studies, TMP/SMX should not be
used empirically. However, data from
the National Ambulatory Medical Care
Survey suggests that around 50% of
children were prescribed TMP/SMX
for paediatric UTIs even though recent
data suggests that most regions in the
United States have resistance rates to
TMP/SMX that exceed the approved
levels for prescribing this antibiotic
empirically.25

Recent examination of UTI
resistance patterns has demonstrated
that most UTIs are sensitive to
narrow spectrum antibiotics, such as
first-generation cephalosporins and
urinary antiinfectives (nitrofurantoin).
These underutilized antibiotics have
demonstrated significantly low
resistance rates over time.26

Endoscopic Injection in Vesicoureteral
Reflux

It is in the view of the strong yet
fearful risk of development of antibiotic
resistance which strongly increases
the incidence of mortality and patients
dying due to infections worldwide,
that the question and the concept of an
alternative mode of intervention (ie,
surgical) arises in the patients with
VUR. The various surgical options
are – open surgery, laparoscopic and
endoscopic injection at the ureteric
orifice. With all of them, the underlying
anomaly at the vesicoureteric junction
is corrected. However, the endoscopic
injection has certain advantages over
the open surgery.

Surgical cure of VUR reduces the
occurrence of pyelonephritis, though
it has not been proven to reduce
the existing renal injury. Patients
with recurrent pyelonephritis and/
or persistent reflux benefit most from
surgery.27

The various theoretical advantages
of laparoscopic approach to reflux
repair include decreased hospital
stay, decreased postoperative pain,
smaller incisions, and faster recovery.
It has efficacy similar to open surgery,
with success rates of 88% to 100%, but
technical difficulty, longer durations
during the procedure and the probable
risk of higher rate of complications
including ureteral injury/obstruction,
urine leak, and fistula, have prevented
its widespread adoption.28

Endoscopic injection techniques
prevent reflux by injecting a bulking
substance to allow elevation and
coaptation of the ureteral orifice. The
various benefits of the endoscopic
technique over open surgery are -
outpatient procedure and in case of
hospital admission, minimal duration
of hospital stays, non-invasive and
reduced patient morbidity.

An ideal injectable material must
have the following characteristics -
durable, effective, safe, inert, easily
injectable, stable with time and must not
migrate, biocompatible, non-antigenic
and non-carcinogenic. Dextranomer/
hyaluronic acid (Dx/HA or Deflux®)
was approved by the United States
Food and Drug Administration in
2001 for the treatment of VUR Grades
II to IV. Dextranomer/hyaluronic acid
copolymer is a viscous gel consisting
of two sugar-based molecules. The
microspheres are suspended in nonanimal
stabilized hyaluronic acid.
The microspheres are large in size
(80–250 μm) and therefore less likely
to embolize or migrate.29

In one of the earl iest studies
conducted by Stenberg (1995) in
Sweden, the authors investigated
the short-term (three months) and
long-term (one year) effects of Deflux®
implantation in 101 ureters with Grade
III and Grade IV VUR. Three months
later at voiding cystography, reflux had
totally resolved in 68% of implants, had
down-graded to Grades I and II in 13%
of ureters, and was unchanged in 19%
of ureters. No adverse reactions were
noted. The results indicated that the
dextranomer microspheres promote
ingrowth of fibroblasts and generate
new collagen. The authors concluded
that the Deflux may represent a new
and safe alternative to treatment of
VUR in children.30

In one of the early studies, Puri
(2003) prospectively evaluated
the effectiveness of dextranomer/
hyaluronic acid copolymer in the
endoscopic treatment of VUR. The
reflux was completely corrected in 143
(86%) of the 166 ureters after a single
endoscopic injection. No untoward
effects were observed in these patients
with the use of this copolymer as an
endoscopic injectable material.31

Kim (2015) in their article relating
to long-term follow-up in children
treated with endoscopic injection retrospectively examined and analyzed
419 ureters of 243 patients. These
patients underwent Deflux® injection
therapy between September 2004 and
September 2014. It was found that the
Deflux® injection was highly efficacious
with almost no complication for the
anti-reflux procedure in children. The
complete cure rates at three months,
one year, and three years follow-up
in the patients were 70.8%, 64.3%,
and 65.6%, respectively. There was an
extremely low recurrence rate of UTI
and high probability of no VUR at three
years if no VUR occurred at 1 year.32

Beetz (2002) evaluated the ongoing
risk of UTIs in long-term follow-up of
158 young adults surgically treated
for VUR in childhood. It was observed
that in the entire long-term follow-up
period, episodes of UTI developed in
66% of all patients, including 74% of
female patients. Out of 46 pregnancies,
symptomatic UTIs were observed in
eight cases.33

Mor (2003) also reviewed patients
who had surgical correction of VUR
by ureteric reimplantation during
childhood, and thus assessed their
long-term outcome. In the 1970s,
322 children underwent surgical
correction of VUR; these patients
were followed-up for a long duration
of 20 years. The follow-up focused
on the incidence of UTIs, current
renal function tests, complications
during pregnancy, and the incidence
of development of hypertension at
least 20 years after surgery. In the
study group, 49% had long-term
urological complications. The incidence
of UTIs was 43% in women and 24%
in men, respectively. The onset of
hypertension was detected in 6% of the
patients during follow-up. There was
development of renal scars, despite
surgery, in 20% of the patients. Among
47 females who became pregnant, 28%
reported UTIs during pregnancy. Thus,
this study showed that even patients
who were treated successfully by open
surgery during their early life were
prone to develop UTIs, progressive
renal scarring, hypertension, and
complications during pregnancy. The
authors realized and emphasized that
there is a need to establish a protocol
for the long-term follow-up of such
patients.34

Thus from several studies as
mentioned above, it was realized
that patients who have undergone open surgery for VUR in childhood
are not free from complications in
later life. However longterm follow
up after endoscopic injection in VUR
shows almost no complications and
an extremely low rate of recurrence
of UTI.32

In a systematic review to identify the
role of Dextranomer/hyaluronic ccid for
paediatric VUR, the authors searched
the Cochrane Controlled Trials Register
and other databases from 1990 to 2008
and found that the overall success
rate with Deflux® injection was 77%
after 3 months with variations existing
among studies. It was also observed
that increased VUR grade negatively
affected success rates.35

Conclusion

In view of the emerging landscape
of antibiotic resistance in VUR in
children, it would definitely not be
recommended to prescribe long-term or
repeated chemoprophylaxis in children.
Among surgical options, endoscopic
injection in these children is an option
with minimum hospital stay, noninvasive
nature and reliable success
rates when injected appropriately.
Thus, an increased use of the
endoscopic injection (Deflux®) should
be encouraged in children suffering
from Grades II to IV VUR.